Ritonavir and Efavirenz Significantly Alter the Metabolism of Erlotinib—an Observation in Primary Cultures of Human Hepatocytes That Is Relevant to HIV Patients with Cancer

Abstract

Erlotinib is approved for the treatment of non-small cell lung and pancreatic cancers, and is metabolized by CYP3A4. Inducers and inhibitors of CYP3A enzymes such as ritonavir and efavirenz, respectively, may be used as part of the highly active antiretroviral therapy drugs to treat patients with human immunodeficiency virus (HIV). When HIV patients with a malignancy need treatment with erlotinib, there is a potential of as-yet-undefined drug-drug interaction. We evaluated these interactions using human hepatocytes benchmarked against the interaction of erlotinib with ketoconazole and rifampin, the archetype cytochrome P450 inhibitor and inducer, respectively. Hepatocytes were treated with vehicle [0.1% dimethylsulfoxide, ritonavir (10 mM)], ketoconazole (10 mM), efavirenz (10 mM), or rifampin (10 mM) for 4 days. On day 5, erlotinib (5 mM) was incubated with the above agents for another 24-48 hours. Concentrations of erlotinib and O-desmethyl erlotinib were quantitated in collected samples (combined lysate and medium) using liquid chromatography and tandem mass spectrometry. The half-life (t 1/2 ) of erlotinib increased from 10.6 6 2.6 to 153 6 80 and 23.9 6 4.8 hours, respectively, upon treatment with ritonavir and ketoconazole. The apparent intrinsic clearance (CL int, app ) of erlotinib was lowered 16-fold by ritonavir and 1.9-fold by ketoconazole. Efavirenz and rifampin decreased t 1/2 of erlotinib from 10.3 6 1.1 to 5.0 6 1.5 and 3.4 6 0.2 hours, respectively. Efavirenz and rifampin increased the CL int, app of erlotinib by 2.2-and 2-fold, respectively. Our results suggest that to achieve desired drug exposure, the clinically used dose (150 mg daily) of erlotinib may have to be significantly reduced (25 mg every other day) or increased (300 mg daily), respectively, when ritonavir or efavirenz is coadministered.

Preclinical assessment of the interactions between the antiretroviral drugs, ritonavir and efavirenz, and the tyrosine kinase inhibitor erlotinib

“…Our findings are generally consistent with the CYP3A4 inhibition literature [19, 31]. The 1.7-fold increase in erlotinib exposure when administered with ketoconazole is consistent with the 1.9-fold decrease in predicted human erlotinib CL oral observed in hepatocytes [19] and a twofold increase in erlotinib exposure in a healthy volunteer trial that was predicted by SimCYP™ [31].…”

“…The metabolic fate of OSI-420 has only been attributed to CYP3A4 in the literature, albeit other CYP450 s may be involved further confounding the results [31]. It should also be noted that the metabolite/parent drug ratio of ~29 % for the control arm is similar to prior experiments utilizing mice [25] but is still fivefold higher than that reported in the mass balance study and human hepatocyte experiment [19, 31]. Therefore, the alterations noted in mice may not be reflective of humans.…”

“…Indeed, erlotinib is primarily metabolized by cytochrome P450 3A4 (CYP3A4) into multiple products, including an active O-desmethyl metabolite (OSI-420), and is susceptible to drug–drug interactions, especially via inhibition or induction of CYP3A4 and CYP1A2 [18]. Currently, it is recommended to avoid the use of erlotinib with a potent inhibitor or a potent inducer, which is further supported by hepatocyte data which demonstrated a 16-fold decrease by ritonavir and a 2.2-fold increase by efavirenz in apparent intrinsic clearance of erlotinib [19, 20]. Erlotinib is a known substrate for ABCB1 and ABCG2 [21].…”

Drug Interactions in the Treatment of Malignancy in HIV-Infected Patients

“…These interactions are highly unpredictable. For example, erlotinib exposure in human hepatocytes increased 4.2-fold when co-administered with ritonavir and decreased 3-fold with efavirenz [23]. On the other hand, docetaxel exposure in mice increased 6.9-fold with ritonavir co-administration, but was unaffected by efavirenz [29].…”

“…Inhibitors of tyrosine kinase and mTOR are also substrates as well as inducers/inhibitors of CYP450 and may be involved in bidirectional DDIs with cART [4,23]. Anthracyclines, antimetabolites, antitumor antibiotics, and platinums undergo non-CYP450 routes of elimination and are not susceptible to CYP450 drug interactions [4].…”